Isocyanides amide synthesis

A rather different approach to peptide bond formation and amide synthesis in general is to treat a mixture of a carboxylic acid and an amine with an isocyanide 2-Morpholinoethyl Isocyanide is especially suitable), which effectively acts as a dehydrating agent (eq 3). The procedure can result in extensive racemization of both reactants and products which may be supressed by the addition of HOSu presumably an HOSu ester is the penultimate intermediate. The addition of HOSu also decreases racemization in polypeptide synthesis when Bates reagent [(Me2N)sP+]20 (BF4 )2 is used as the coupling agent. ... 

The use of a vinylphosphonium salt as the source of the QQ fragment instead of the more commonly employed 1,2-dicarbonyl substrate is illustrated by the pyrrole synthesis in Scheme 79b (8UOC2570). A particularly interesting feature is the intramolecular Wittig reaction with an amide carbonyl group. A very useful synthesis of pyrroles depends upon the addition of the anion of p-toluenesulfonylmethyl isocyanide (TOSMIC) to a,/3-unsatur-... 

The mechanistic analogy to the Streckcr synthesis becomes obvious in the addition of the isocyanide to the imine to produce the a-amino nitrilium intermediate. Since all four components are involved in this step, it might be expected that every chiral component (chiral groups R1, R2, R3, R4) contributes to diastereofacial differentiation in the nucleophilic attack on the imine. However, in peptide syntheses by four-component condensation5, the chiral isocyanide or a chiral carboxylic acid component has only limited influence on the diastereoselectivity of the a-amino amide formation5. 

The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

Alternatively, starting this time from aryl isocyanides, the secondary amide can be activated by conversion into an imide by the treatment with B0C2O [29, 38,41]. This strategy was employed in the synthesis of compounds 15,17 and 19 [29], and is particularly appropriate for solid-phase library synthesis. 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

One of the pioneer works in the synthesis of DKPs through MCRs was reported by Hulme and coworkers in a three-step solution phase protocol based on UDC [33, 34]. They have obtained a series of different DKPs by reacting Armstrong s convertible isocyanide with aldehydes, M-Boc-protected amino acids as bifunctional acid component containing a protected internal amino nucleophile, and amines in methanol at room temperature. After Ugi-reaction, the isonitrile-derived amide is activated with acid (UAC) and allows cyclization to the DKP with the... 

Scheme 6 DKP synthesis by UAC with tert-butyl isocyanide as convertible reagent The amide is activated by acid and microwave heating...

A similar approach was recently reported by Hulme and coworkers. They published an Ugi-reaction-based DKP synthesis that does not require special isonitriles but uses simple linear ones like W-butyl isocyanide. The corresponding Amide-Ugi-products usually do not cyclize well, but under microwave conditions, good yields were obtained (Scheme 7) [39]. 

In a three-component synthesis the amide (86-1) obtained from the ester (85-5) and benzyl isocyanide is reacted with the piperdone (86-2). The product from this transform consists of the addition product (86-3) where amide nitrogen in (86-1) as well as the carbon from the isocyanide have added to the carbonyl group on the piperidine. Treatment of the adduct (86-3) with a strong acid hydrolyzes the urethane function on the fert-butyloxycarbonic protecting group, leaving behind the primary... 

Oxidation of the a-hydroxy-/ -acylamino amides obtained by this strategy constitutes an easy access to a-ketoamides. The Banfi group [28] reported the synthesis of a-ketoamides such as 37 and 38 starting from isocyanides and acid components... 

Analogously, the reaction between phenylglyoxal, isobutylamine, n-butyl isocyanide, and benzoic acid afforded 3-oxo-3-phenylpropanoic amide 85 which was cy-clized to diphenylimidazol-5-carboxamide 86 in very high yield (Scheme 2.31) [60], The procedure was extended to solid-phase synthesis by employing resin-bound isocyanides. Wang resin was preferred to Rink resin because of its stability. The reaction of the resin-bound isocyanides 87 with supporting Ugi reagents afforded the... 

The Hulme group reported an efficient three-step, one-pot solution-phase synthesis of 2-imidazolines employing the UDC strategy [62], The reaction between N-Boc-protected a-aminoaldehydes, amines, acids, and isocyanides afforded the N-Boc-protected a-acylamino amides 94 which, upon heating in addic medium, underwent N-deprotection and cyclization to 2-imidazolines 95 (Scheme 2.34). This procedure was adapted to combinatorial synthesis in a rack of 96 reaction vials. 

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

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